Customized MUC1 Sequencing Enables Diagnosis of Autosomal Dominant Tubulointerstitial Kidney Disease and Unexplained CKD

MUC1

Pathogenic frameshift variants (DupC, DupA) within the MUC1 VNTR region, generating pathogenic MUC1 neoproteins

Genetic diagnosis of MUC1-related ADTKD is technically challenging, which contributes to the underdiagnosis of inherited kidney disease. The authors implemented a customized short-read library with dedicated bioinformatic approaches for the MUC1 VNTR region, applied to 550 patients with suspected inherited kidney disease and no identified genetic cause. Twenty-eight patients had ADTKD-MUC1, carried by a DupC (almost 90% of cases) or DupA (10%) frameshift variant, and more than half of these cases were detected only through specialized bioinformatic analysis. Variants were confirmed by Sanger, SNaPshot or long-read sequencing depending on location and variant type. Integrated into the routine diagnostic workflow, the strategy increased diagnostic yield while avoiding the sequential use of multiple methods.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A pragmatic answer to a known exome blind spot: the MUC1 VNTR largely escapes standard analysis, and this series shows that dedicated capture with specific bioinformatic analysis makes it accessible by short-read sequencing. ADTKD-MUC1 should therefore not be considered excluded by a negative exome when inherited kidney disease is suspected. The sensitivity of the method compared with long-read sequencing is not measured in the abstract.

Analysis by Dr Thibaut Benquey